Abstract Gastrointestinal (GI) disorders including constipation and fecal incontinence are commonly found in patients with Alzheimer’s disease (AD), the most common cause of dementia. These same disorders are also frequently encountered in the elderly, raising the possibility that a common process may underlie gut disturbances for both AD and aging. In humans with AD and AD animal models, amyloid-β (Aβ) plaques, one of the disease hallmarks, have been detected in the enteric nervous system (ENS), an autonomous branch of the peripheral nervous system that spans the GI tract and regulates gut motility. Aβ gut accumulation appears to cause ENS neuroinflammation and impaired gut contractility but current literature precludes definitive conclusion. Whether and how AD involves the gut is of increasing importance given emerging reports that neurodegenerative disorders are transmitted from the gut to the brain. The proposed multidisciplinary study will integrate the science of AD with the basic biology of aging. We found that age-related changes to muscularis macrophages (MMs), a population of tissue-resident macrophages in the ENS, drive geriatric ENS inflammation, which is associated with disruption of GI motility. This MM alteration is regulated by the scavenger receptor CD36 and mirrors an AD diseased state found in microglia, the predominant macrophage population of the brain. Following on these findings, we posit that a common CD36-dependent immune pathway in brain and gut regulates ENS neuroinflammation and disruption of gut motility in AD. This hypothesis will be tested with two aims performed in AD mouse models (APP/PS1 mice and Aβ-gut injected mice) in combination with CD36 knockout mice. First, the investigators will evaluate whether genetic deletion of CD36 inhibits Aβ induced neuroimmune changes characterized by a shift in MMs from a tissue-protective, homeostatic state (HS) to a pro- inflammatory geriatric state (GS). They will also assess whether CD36 deficiency inhibits AD-induced ENS neuroinflammation characterized by infiltration of immune cells and elevated pro-inflammatory cytokines. Second, the investigators will assess the impact of CD36 deficiency on AD-induced enteric neuron loss and disruption of gut motility. Successful completion of the proposed studies will identify a critical pathophysiological pathway in brain and gut involved in neurodegenerative disease and aging. The results will inform novel prevention and intervention strategies for AD-associated GI disorders.